Study links two proteins that help cells eliminate trash to Parkinson’s disease.


Much like a community’s network for garbage handling, cells also have garbage sites called lysosomes, where proteins, which are functioning badly because of age or other reasons, go for degradation and potential recycling.  Inside lysosomes, other proteins, called proteases, help cut up proteins that can no longer do their job and enable salvaging of things like precious amino acids.

It’s a normal cell degradation process called autophagy that actually helps cells survive and is particularly important in cells such as neurons, which regenerate extremely slowly.  Now, researchers from Georgia Regents University have identified two proteins that share the ability to help cells deal with their trash appear to need each other to do their jobs and when they don’t connect, it appears to contribute to development of Parkinson’s disease.

Previous studies show that dopamine is a brain chemical with many roles, including motor control, and patients with Parkinson’s have a loss of the neurons that secrete this neurotransmitter.  The new study shows that key to the process are two more proteins, VPS35 and Lamp2a. Earlier studies show that VPS35 is essential for retrieving membrane proteins vital to cell function. Levels naturally decrease with age, and mutations in the VPS35 gene have been found in patients with a rare form of Parkinson’s. VPS35 also is a critical part of a protein complex called a retromer, which has a major role in recycling inside cells. Lamp2a enables unfit proteins to be chewed up and degraded inside lysosomes.

A study from the researchers in 2011 found that reduced expression of VPS35 enables activity of the dormant-in-healthy-adults protein BACE1 to increase along with accumulation of the brain plaque that is a hallmark of Alzheimer’s. The team concluded back then that impaired VPS35 function likely also was a factor in Parkinson’s.  Their previous results showed that in a definite vicious circle, trash starts overwhelming the brain cell’s natural garbage disposal system. In their previous study proteins start getting misfolded and dysfunctional, potentially destructive proteins such as BACE1 and Lamp2a end up in the wrong place and get activated/inactivated, while good proteins get chopped up and/or bad proteins accumulate.  Therefore, the group wanted to investigate this further.

The current study shows that without VPS35 to retrieve Lamp2a from the trash site for reuse, Lamp2a, or lysosomal-associated membrane protein 2, will be degraded and its vital function lost.  When the scientists generated VPS35-deficient mice, the mice exhibited Parkinson’s-like deficits, including impaired motor control. When the current study looked further, results showed the lysosomes inside dopamine neurons, which are targets in Parkinson’s, didn’t function properly in the mice.

In fact, data findings show that without VPS35, the degradation of Lamp2a itself is accelerated. Consequently, the team observed that another protein, alpha-synuclein, which is normally destroyed by Lamp2a, is increased. The lab explain that alpha-synuclein is a major component of abnormal protein clumps, called Lewy bodies, found in the brains of patients with Parkinson’s.

Conversely, results showed that increased expression of Lamp2a in the dopamine neurons of the VPS35-deficient mice, alpha-synuclein levels were reduced, a finding that further supports the linkage of the three proteins in the essential ability of the neurons to deal with undesirables in their lysosomes.

Findings show that without lamp2a, dopamine neurons essentially start producing more garbage rather than eliminating it. The group state that recycling of valuables such as amino acids basically stops, and alpha-synuclein is free to roam to other places in the cell or other brain regions where it can damage still viable proteins.

The team surmise that dopamine neurons are lost instead of preserved in disease such as Parkinson’s and Alzheimer’s. Past brain scans document the empty spaces where neurons used to be in patients.  They go on to add that one of the many problems with treatment of these diseases is that by the time the empty spaces and sometimes the associated symptoms are apparent, much damage has occurred.

The lab conclude that putting these pieces together provides several new, early targets for disease intervention.

Source:  Georgia Regents University

 

Direct inputs to dopamine neurons: green dots represent neurons providing inputs to dopamine neurons in the ventral tegmental area (VTA), while red dots represent neurons providing inputs to SNc dopamine neurons (credit: Mitsuko Watabe-Uchida and Sachie Ogawa, Harvard)

Direct inputs to dopamine neurons: green dots represent neurons providing inputs to dopamine neurons in the ventral tegmental area (VTA), while red dots represent neurons providing inputs to SNc dopamine neurons (credit: Mitsuko Watabe-Uchida and Sachie Ogawa, Harvard)

One comment

  • Great stuff Michelle. My, it does appear that this nut is actually beginning to crack! Many thanks, Lisa PDDBSwife

    Like

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